A large disordered region confers a wide spanning volume to vertebrate Suppressor of Fused as shown in a trans-species solution study.
Hedgehog (Hh) pathway inhibition by the conserved protein Suppressor of Fused (SuFu) is crucial to vertebrate development. By constrast, SuFu loss-of-function mutant has little effect in drosophila. Previous publications showed that the crystal structures of human and drosophila SuFu consist of two ordered domains that are capable of breathing motions upon ligand binding. However, the crystal structure of human SuFu does not give information about twenty N-terminal residues (IDR1) and an eighty-residue-long region predicted as disordered (IDR2) in the C-terminus, whose function is important for the pathway repression. These two intrinsically disordered regions (IDRs) are species-dependent. To obtain information about the IDR regions, we studied full-length SuFu's structure in solution, both with circular dichroism and small angle X-ray scattering, comparing drosophila, zebrafish and human species, to better understand this considerable difference. Our studies show that, in spite of similar crystal structures restricted to ordered domains, drosophila and vertebrate SuFu have very different structures in solution. The IDR2 of vertebrates spans a large area, thus enabling it to reach for partners and be accessible for post-translational modifications. Furthermore, we show that the IDR2 region is highly conserved within phyla but varies in length and sequence, with insects having a shorter disordered region while that of vertebrates is broad and mobile. This major variation may explain the different phenotypes observed upon SuFu removal.


The Troika Host-Pathogen-Extrinsic Factors in Tuberculosis: Modulating Inflammation and Clinical Outcomes.
The already enormous burden caused by tuberculosis (TB) will be further aggravated by the association of this disease with modern epidemics, as human immunodeficiency virus and diabetes. Furthermore, the increasingly aging population and the wider use of suppressive immune therapies hold the potential to enhance the incidence of TB. New preventive and therapeutic strategies based on recent advances on our understanding of TB are thus needed. In particular, understanding the intricate network of events modulating inflammation in TB will help to build more effective vaccines and host-directed therapies to stop TB. This review integrates the impact of host, pathogen, and extrinsic factors on inflammation and the almost scientifically unexplored complexity emerging from the interactions between these three factors. We highlight the exciting data showing a contribution of this troika for the clinical outcome of TB and the need of incorporating it when developing novel strategies to rewire the immune response in TB.


[Diagnostic and prognostic significance of so-called rheumatoid vasculitis].
23 patients with rheumatoid arthritis and high rheumatic factors (mean titres of rheumatic factors 1 : 1 434) within a prospective study on the diagnostic and prognostic significance of the rheumatoid vasculitis which was performed together with the Research Institute for Rheumatism Moscow underwent examinations for the proof of an extraarticular organ manifestation. In correspondence with the data in literature we found rheumatic nodes (70%) as most frequent extraarticular organ manifestation. In 1 patient each a participation of the lungs and a rheumatic exudate of the pleura, respectively, could be diagnosed. In another patient there were references to a vasculitis at the fundus of the eye. In only 2 patients there was a vasculitis of the digital arteries with necroses, in one of them a generalized vasculitis. 5 of the 13 neurologically examined patients showed polyneuropathic symptoms. Of the biochemical findings the C-reactive protein and the blood sedimentation rate showed clear increases and correlations.


Chronic activation of JNK JAK/STAT and oxidative stress signalling causes the loser cell status.
Cell competition is a form of cell interaction that causes the elimination of less fit cells, or losers, by wild-type (WT) cells, influencing overall tissue health. Several mutations can cause cells to become losers; however, it is not known how. Here we show that Drosophila wing disc cells carrying functionally unrelated loser mutations (Minute and mahjong) display the common activation of multiple stress signalling pathways before cell competition and find that these pathways collectively account for the loser status. We find that JNK signalling inhibits the growth of losers, while JAK/STAT signalling promotes competition-induced winner cell proliferation. Furthermore, we show that losers display oxidative stress response activation and, strikingly, that activation of this pathway alone, by Nrf2 overexpression, is sufficient to prime cells for their elimination by WT neighbours. Since oxidative stress and Nrf2 are linked to several diseases, cell competition may occur in a number of pathological conditions.Cell competition causes the removal of less fit cells ('losers') but why some gene mutations turn cells into losers is unclear. Here, the authors show that Drosophila wing disc cells carrying some loser mutations activate Nrf2 and JNK signalling, which contribute to the loser status.


A review of boron neutron capture therapy (BNCT) and the design and dosimetry of a high-intensity, 24 keV, neutron beam for BNCT research.
This paper reviews the development of boron neutron capture therapy (BNCT) and describes the design and dosimetry of an intermediate energy neutron beam, developed at the Harwell Laboratory, principally for BNCT research. Boron neutron capture therapy is a technique for the treatment of gliomas (a fatal form of brain tumour). The technique involves preferentially attaching 10B atoms to tumour cells and irradiating them with thermal neutrons. The thermal neutron capture products of 10B are short range and highly damaging, so they kill the tumour cells, but healthy tissue is relatively undamaged. Early trials required extensive neurosurgery to exposure the tumour to the thermal neutrons used and were unsuccessful. It is thought that intermediate-energy neutrons will overcome many of the problems encountered in the early trials, because they have greater penetration prior to thermalization, so that surgery will not be required. An intermediate-energy neutron beam has been developed at the Harwell Laboratory for research into BNCT. Neutrons from the core of a high-flux nuclear reactor are filtered with a combination of iron, aluminium and sulphur. Dosimetry measurements have been made to determine the neutron and gamma-ray characteristics of this beam, and to monitor them throughout the four cycles used for BNCT research. The beam is of high intensity (approximately 2 x 10(7) neutrons cm-2 s-1, equivalent to a neutron kerma rate in water of 205 mGy h-1) and nearly monoenergetic (93% of the neutrons have energies approximately 24 keV, corresponding to 79% of the neutron kerma rate).


The Hematocrit Affects the Volume of Plasma Treated With Coupled Plasma Filtration and Adsorption With Predilution.
Coupled plasma filtration and adsorption (CPFA) is an extracorporeal blood purification technique proposed for the treatment of septic-shock. By removing pro- and anti-inflammatory mediators from plasma, CPFA is supposed to have a therapeutic effect on the abnormal inflammatory response seen in this condition. Recently, blood predilution with citrate solution has been adopted to prevent clotting in the CPFA circuit-one of the main problems of the technique. Taking into account the patient's hematocrit, we worked out a formula for the volume of plasma effectively treated by CPFA after predilution. Neglecting this effect, as is commonly done, introduces significant distortions in the estimation of the volume, possibly causing under-treatment. The distortion is stronger when the hematocrit and the predilution fraction are large and weaker when both values shrink. By correctly indicating the daily dose of plasma adsorption received by patients, this formula is essential for assessing the therapeutic efficacy of CPFA and, subsequently, establishing its optimal doses.


Predictors allowing early discharge after interventional treatment of acute coronary syndrome patients.
Many scoring systems for predicting the outcomes of patients with acute coronary syndrome (ACS) have been proposed. In some populations, a significant reduction in length of hospital stay may be achieved without compromising patient prognoses. However, the use of such scoring systems in clinical practice is limited. The aim of this study was to propose a universal list of predictors that can identify low-risk ACS patients who may be eligible for an earlier hospital discharge without increased short-term risk for major adverse cardiac events. A cohort of 1420 patients diagnosed with ACS were enrolled into a single-centre registry between October 2018 and December 2020. Clinical, laboratory, echocardiographic, and angiographic measurements were taken for each patient and entered into the study database. Using retrospective univariant analyses of patients treated with percutaneous coronary intervention (PCI) (n = 932), we compared each predictor to 30-day mortality rate using the Czech national registry of dead people. Eleven predictors correlate significantly with 30-day survival: age <80 years, ejection fraction >50%, no cardiopulmonary resuscitation, no mechanical ventilation needed, Killip class I at admission, haemoglobin levels >110 g/L while hospitalized, successful PCI procedure(s), no residual stenosis over 90%, Thrombolysis in Myocardial Infarction 3 flow after PCI, no left main stem disease, and no triple-vessel coronary artery disease. In all, presence of all predictors applies to 328 patients (35.2% of the cohort), who maintained a 100% survival rate at 30 days. A combination of clinical, echocardiographic, and angiographic findings provides valuable information for predicting the outcomes of patients with all types of ACS. We created a simple, useful tool for selecting low-risk patients eligible for early discharge.


Correlation of serum, urinary and salivary CA 125 levels in patients with adnexal masses.
A prospective study was made of 105 consecutive patients admitted to one department of obstetrics and gynaecology for surgery for adnexal masses. The objective was to investigate if CA 125 level is measurable in the urine or saliva and to correlate these measurements with serum CA 125 level in patients presenting with adnexal masses. The final diagnosis and grouping of patients for analysis were based on histopathological examination of the adnexal masses. Serum, urine and salivary samples were collected simultaneously from all patients on the morning before surgery. CA 125 levels in each sample were determined in duplicate using Abbott CA 125-E1A monoclonal test kits (Abbott Laboratories, USA). The mean inter-assay variability was 10%. CA 125 was detectable in the serum, urine and saliva from all the patients and the concentration was highest in the saliva and lowest in urine. There were no discernible differences in the distributions of salivary CA 125 concentrations between patients with ovarian malignancies and those with benign ovarian cysts. In contrast, both serum and urinary CA 125 levels were significantly higher in the ovarian cancer group. There was no correlation in CA 125 concentrations between serum and urine, or between serum and saliva. For detection of ovarian malignancies, the sensitivity, specificity, and positive and negative predictive values for serum CA 125 measurement (> or = 35 U/mL) were 88.9%, 79.2%, 27.6% and 98.7 respectively. The corresponding figures for urinary CA 125 measurement (> or = 10 U/mL) were 88.9%, 66.7%, 19.5% and 98.4% respectively.(ABSTRACT TRUNCATED AT 250 WORDS)


Diaphragmatic hernia in the Coffin-Siris syndrome.
At 32 weeks of gestation, delivery of a female fetus was induced because of severe malformations seen on ultrasonogram: congenital diaphragmatic hernia and cerebellar hypoplasia. The diagnosis of Coffin-Siris syndrome was based on the physical examination: coarse face with low-set ears, low nuchal hairline, scalp hypotrichosis and hypoplasia of the nails of fingers and toes with absence of the right fifth fingernail. Autopsy confirmed the prenatally diagnosed major associated abnormalities: hypoplasia of the cerebellum and congenital diaphragmatic hernia. Various clinical entities are included in the differential diagnosis.


Hairpin DNA-based electrochemical amplification strategy for miRNA sensing by using single gold nanoelectrodes.
A new sensor has been developed to detect miRNA-15 using nanoelectrodes and a hairpin DNA-based electrochemical amplification technique. By utilizing a complex DNA cylinder connected with hairpin DNA1, the sensor is able to absorb more methylene blue (MB) than simple double-stranded DNA. Another hairpin DNA2 is modified on an Au nanoelectrode surface and, when miRNA-15 is introduced, it triggers a chain reaction. This reaction unlocks two hairpins alternatively to polymerize into a complex structure that attaches more MB. The miRNA-15 is then replaced by DNA1 due to strand displacement reactions and continues to react with the next DNA2 to achieve circular amplification. The electrochemical signal from MB oxidation has a linear relationship with the miRNA-15 concentrations, making it possible to detect miRNA-15. Moreover, this method can be readily adapted for the detection of various other miRNA species. The newly devised nanosensor holds promising applications for the in vivo detection of miRNA-15 within biological systems, which is achieved by leveraging the advantageous characteristics of nanoelectrodes, including their low resistance-capacitance time constant, rapid mass transfer kinetics, and small diameter.


Granulomatosis polyangiitis associated with meningeal involvement: response to rituximab therapy after failure of cyclophosphamide.
Wegener's granulomatosis or granulomatosis polyangiitis associated (GPA) is a granulomatous inflammation of the upper and lower respiratory tracts associated with necrotising vasculitis of small and medium-sized blood vessels and, frequently, necrotising glomerulonephritis. We describe the case of a 37 year old female patient presenting with upper respiratory tract involvement, chronic rhinosinusitis with green secretions, and bilateral hypoacusia. Ten months later, she suffered occipital headache and two episodes of lipothymia associated with nausea, photophobia, faintness with visual blurring. Magnetic resonance imaging (MRI) revealed aseptic meningitis. The patient was treated with steroids and cyclophosphamide without any effect on the neurological symptoms which, however, greatly improved after subsequent treatment with rituximab as confirmed by means of cerebral MRI. Rituximab is an optimal means of treating cyclophosphamide-resistant patients with GPA associated with meningeal involvement.


Epigallocatechin gallate supplementation alleviates diabetes in rodents.
As the prevalence of type 2 diabetes mellitus is increasing at an alarming rate, effective nutritional and exercise strategies for the prevention of this disease are required. Specific dietary components with antidiabetic efficacy could be one aspect of these strategies. This study investigated the antidiabetic effects of the most abundant green tea catechin, epigallocatechin gallate (EGCG, TEAVIGO), in rodent models of type 2 diabetes mellitus and H4IIE rat hepatoma cells. We assessed glucose and insulin tolerance in db/db mice and ZDF rats after they ingested EGCG. Using gene microarray and real-time quantitative RT-PCR we investigated the effect of EGCG on gene expression in H4IIE rat hepatoma cells as well as in liver and adipose tissue of db/db mice. EGCG improved oral glucose tolerance and blood glucose in food-deprived rats in a dose-dependent manner. Plasma concentrations of triacylglycerol were reduced and glucose-stimulated insulin secretion was enhanced. In H4IIE cells, EGCG downregulated genes involved in gluconeogenesis and the synthesis of fatty acids, triacylgycerol, and cholesterol. EGCG decreased the mRNA expression of phosphoenolpyruvate carboxykinase in H4IIE cells as well as in liver and adipose tissue of db/db mice. Glucokinase mRNA expression was upregulated in the liver of db/db mice in a dose-dependent manner. This study shows that EGCG beneficially modifies glucose and lipid metabolism in H4IIE cells and markedly enhances glucose tolerance in diabetic rodents. Dietary supplementation with EGCG could potentially contribute to nutritional strategies for the prevention and treatment of type 2 diabetes mellitus.


Follicle-stimulating hormone regulation of inhibin alpha-subunit mRNA in staged rat seminiferous tubules.
Steady-state levels of inhibin-alpha and -beta B mRNAs are higher in stages II-VI of the seminiferous epithelial cycle than in stages VII-VIII. We investigated follicle-stimulating hormone (FSH) regulation of inhibin alpha-subunit mRNA in stages II-VI and VII-VIII to study whether the stage specificity is due to differential hormonal regulation by FSH. Follicle-stimulating hormone caused a significant increase of inhibin-alpha mRNA levels in both stages during a 20-h incubation. The mechanism of the FSH effect was studied further in stages VII-VIII. Maximal stimulation of the inhibin-alpha mRNA level was achieved with 100 micrograms/l FSH, dibutyryl-3',5'-cyclic adenosine monophosphate (db-cAMP, 0.2 mmol/l) and Sp-adenosine-3',5'-monophosphothionate (Sp-cAMPS, 10 mumol/l) (a cAMP agonist). The presence of Rp-cAMPS (200 mumol/l) (a cAMP antagonist) abolished the stimulation, Rp-cAMPS alone had no effect. Inhibin-beta B mRNA levels in stages VII-VIII were not affected by FSH, db-cAMP, Sp-cAMPS or Rp-cAMPS. Phorbol 12-myristate 13-acetate (100 nmol/l) had no effect on inhibin-alpha or -beta B mRNA levels. Actinomycin D abolished the stimulatory effect of FSH on inhibin-alpha mRNA expression. In conclusion, FSH stimulated inhibin-alpha mRNA expression similarly both in stages II-VI and VII-VIII of the seminiferous epithelial cycle and the stimulation in stages VII-VIII was cAMP-mediated.


Generalized Concentration Addition Modeling Predicts Mixture Effects of Environmental PPARγ Agonists.
The vast array of potential environmental toxicant combinations necessitates the development of efficient strategies for predicting toxic effects of mixtures. Current practices emphasize the use of concentration addition to predict joint effects of endocrine disrupting chemicals in coexposures. Generalized concentration addition (GCA) is one such method for predicting joint effects of coexposures to chemicals and has the advantage of allowing for mixture components to have differences in efficacy (ie, dose-response curve maxima). Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor that plays a central role in regulating lipid homeostasis, insulin sensitivity, and bone quality and is the target of an increasing number of environmental toxicants. Here, we tested the applicability of GCA in predicting mixture effects of therapeutic (rosiglitazone and nonthiazolidinedione partial agonist) and environmental PPARγ ligands (phthalate compounds identified using EPA's ToxCast database). Transcriptional activation of human PPARγ1 by individual compounds and mixtures was assessed using a peroxisome proliferator response element-driven luciferase reporter. Using individual dose-response parameters and GCA, we generated predictions of PPARγ activation by the mixtures, and we compared these predictions with the empirical data. At high concentrations, GCA provided a better estimation of the experimental response compared with 3 alternative models: toxic equivalency factor, effect summation and independent action. These alternatives provided reasonable fits to the data at low concentrations in this system. These experiments support the implementation of GCA in mixtures analysis with endocrine disrupting compounds and establish PPARγ as an important target for further studies of chemical mixtures.


COVID-19 infection in kidney transplant recipients.
By 21 March 2020 infections related to the novel coronavirus SARS-CoV-2 had affected people from 177 countries and caused 11,252 reported deaths worldwide. Little is known about risk, presentation and outcomes of SARS-CoV-2 (COVID-19) infection in kidney transplantation recipients, who may be at high-risk due to long-term immunosuppression, comorbidity and residual chronic kidney disease. Whilst COVID-19 is predominantly a respiratory disease, in severe cases it can cause kidney and multi-organ failure. It is unknown if immunocompromised hosts are at higher risk of more severe systemic disease. Therefore, we report on seven cases of COVID-19 in kidney transplant recipients (median age 54 (range 45-69), three females, from a cohort of 2082 managed transplant follow-up patients) over a six-week period in three south London hospitals. Two of seven patients presented within three months of transplantation. Overall, two were managed on an out-patient basis, but the remaining five required hospital admission, four in intensive care units. All patients displayed respiratory symptoms and fever. Other common clinical features included hypoxia, chest crepitation, lymphopenia and high C-reactive protein. Very high D dimer, ferritin and troponin levels occurred in severe cases and likely prognostic. Immunosuppression was modified in six of seven patients. Three patients with severe disease were diabetic. During a three week follow up one patient recovered, and one patient died. Thus, our findings suggest COVID-19 infection in kidney transplant patients may be severe, requiring intensive care admission. The symptoms are predominantly respiratory and associated with fever. Most patients had their immunosuppression reduced and were treated with supportive therapy.


Schedules of controlled substances: placement of Zopiclone into schedule IV. Final rule.
With the issuance of this final rule, the Deputy Administrator of the Drug Enforcement Administration (DEA) places the substance, zopiclone, including its salts, isomers and salts of isomers into Schedule IV of the Controlled Substances Act (CSA). As a result of this rule, the regulatory controls and criminal sanctions of Schedule IV will be applicable to the manufacture, distribution, dispensing, importation and exportation of zopiclone and products containing zopiclone.


Structural and functional analysis of the role of the chaperonin CCT in mTOR complex assembly.
The mechanistic target of rapamycin (mTOR) kinase forms two multi-protein signaling complexes, mTORC1 and mTORC2, which are master regulators of cell growth, metabolism, survival and autophagy. Two of the subunits of these complexes are mLST8 and Raptor, β-propeller proteins that stabilize the mTOR kinase and recruit substrates, respectively. Here we report that the eukaryotic chaperonin CCT plays a key role in mTORC assembly and signaling by folding both mLST8 and Raptor. A high resolution (4.0 Å) cryo-EM structure of the human mLST8-CCT intermediate isolated directly from cells shows mLST8 in a near-native state bound to CCT deep within the folding chamber between the two CCT rings, and interacting mainly with the disordered N- and C-termini of specific CCT subunits of both rings. These findings describe a unique function of CCT in mTORC assembly and a distinct binding site in CCT for mLST8, far from those found for similar β-propeller proteins.


[Attacks of abdominal pain can be abdominal migraine].
A lot of patients suffer from abdominal pain, nausea and vomiting. They are often seen in many departments and specialities. A few of these may suffer from abdominal migraine and can be treated well with antimigraine medication. This is a case report of a 25-year-old woman predisposed to migraine and with migraine headache who suffered from attacks of abdominal pain, anorexia, nausea and vomiting. She was thoroughly examined without any signs of abdominal pathology and was then referred to a neurological specialist who successfully treated her with propranolol.


Oncogenic osteomalacia caused by a phosphaturic mesenchymal tumor of the oral cavity: a case report.
We report a case of oncogenic osteomalacia associated with a phosphaturic mesenchymal tumor in a 31-year-old woman. She was presented with severe generalized bone and muscle pain and was restricted to bed. She lost 20 cm in height over the 8 years since she had first noticed a pain in her thigh. A walnut-sized, hard, soft tissue tumor was found very easily beside her lower molar teeth Radiologic examination revealed a remarkable decrease in bone density and multiple pathologic fractures of spine, femur and phalangeal bones. Severe hypophosphatemia, hyperphosphaturia, low plasma 1,25-dihydroxyvitamin D3 level and high plasma PTH level were disclosed at presentation. Histomorphometric examination revealed an extensive area of unmineralized osteoid and little mineralizing activity. A pharmacologic dose of 1 alpha-hydroxyvitamin D3 or or 1,25-dihydroxyvitamin D3 slightly increased the serum phosphate level and renal tubular reabsorption of phosphate, and slightly decreased plasma PTH level without any symptomatic improvement. Histologic examination of the tumor revealed a mixed connective tissue tumor that consisted of central woven bones and surrounding primitive spindle cells with prominent vascularities. After removal of the tumor, all biochemical, hormonal and radiologic abnormalities disappeared with remarkable symptomatic improvement.


Distribution of the bla OXA , bla VEB-1 , and bla GES-1 genes and resistance patterns of ESBL-producing Pseudomonas aeruginosa isolated from hospitals in Tehran and Qazvin, Iran.
Pseudomonas aeruginosa is one of the most common nosocomial pathogens. The emergence of extended spectrum β-lactamases (ESBLs) has been increasingly reported as a major clinical concern worldwide. The main aim of the present study was to determine the distribution of bla OXA, bla PER-1, bla VEB-1, and bla GES-1 genes among ESBL-producing P. aeruginosa isolated from two distinct provinces in Iran. In this study, a total of 75 (27.5%) ESBL-producing isolates were identified from 273 P. aeruginosa isolates collected from patients in Qazvin and Tehran. Phenotypic detection of ESBLs and antimicrobial susceptibility testing were performed according to the Clinical and Laboratory Standards Institute guidelines. PCR and sequencing were employed to detect bla OXA-1, bla OXA, bla GES-1, bla PER-1, and bla VEB-1 genes. Isolate genetic relationships were evaluated by repetitive extragenic palindromic sequence-based PCR (REP-PCR). In total, 59 (78.7%) of the ESBL-producing isolates showed multidrug resistance. The highest rates of susceptibility were observed against colistin (75 isolates, 100%) and polymyxin B (75, 100%) followed by amikacin (44, 58.7%), and piperacillin-tazobactam (40, 53.3%). The bla OXA-1 (37.3%) gene was the most common of the genes investigated, followed by bla OXA-4 (32%), bla GES-1 (16%), and bla VEB-1 (13.3%). REP-PCR identified three different genotypes: types A (89.3%), B (6.7%), and C (4%). We found a significant presence of bla OXA-1, bla OXA-4, bla GES-1, and bla VEB-1 genes among P. aeruginosa isolates, highlighting the need for suitable infection control strategies to effectively treat patients and prevent the further distribution of these resistant organisms.


Can the Aviation Industry be Useful in Teaching Oncology about Safety?
Healthcare practitioners have long considered aviation as a domain from which much can be learned about safety. Over the past 30 years, attempts have been made to apply aviation safety-related concepts to healthcare. Although some applications have been successful, a few decades later, many healthcare safety experts have learned that the appeal of the aviation-healthcare analogy is an illusion. Both domains are so basically dissimilar that simple adoption of aviation concepts will not be successful. However, what has succeeded is healthcare's adaptation of specific aviation safety concepts. Three concepts, investment in safety, human factors and safety management systems, are described and examples are given of adapted applications to healthcare/clinical oncology. Finally, there is a need to ensure that these concepts are applied systematically throughout healthcare rather than sporadically and without a centralised mandate, to help ensure success and improved patient and provider safety.


Propylthiouracil-induced antineutrophil cytoplasmic antibody-associated vasculitis.
Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) refers to a group of potentially life-threatening autoimmune diseases. A recent development in this field is the recognition that certain drugs can induce AAV. Among these agents, the drug most often implicated in causing disease is the commonly used antithyroid agent propylthiouracil (PTU). This Review provides an update on PTU-induced AAV. Clinical characteristics of PTU-induced AAV are similar to that of primary AAV, but usually have a milder course and better prognosis, provided early cessation of the disease-causing drug. PTU-induced ANCAs usually react to several components of myeloid granules, which is helpful in differentiating PTU-induced AAV from primary AAV. Early cessation of PTU is crucial in the treatment of PTU-induced AAV. The duration of immunosuppressive therapy might be shorter than in primary AAV, depending on the severity of organ damage, and maintenance therapy is not always necessary.


Blood pressure in ICSI-conceived adolescents.
Do young adolescents conceived by ICSI display a higher blood pressure than spontaneously conceived (SC) adolescents? In our study, 14-year-old male and female ICSI teenagers were not found to have increased blood pressure at rest. Only limited data are available regarding the cardiovascular risk of children born after assisted conception and up till now, no data on the cardiovascular health in pubertal children conceived by ICSI have been published. In this study, resting blood pressure and blood pressure response to a psychological stressor were measured in a cohort of 14-year-old teenagers conceived by ICSI and compared the results with those of a group of SC peers. In this cross-sectional study, resting blood pressure measurements were available from 217 singleton ICSI children (116 boys, 101 girls) and 223 singleton control children born after spontaneous conception (115 boys, 108 girls). Continuous blood pressure measurements, performed during a psychological stress test, were available for only 67 ICSI and 38 SC children. The study group comprised adolescents conceived by ICSI predominantly because of male factor infertility and they were part of a previously published cohort followed since birth; controls were a cross-sectional sample of peers born to fertile parents and recruited from comparable schools as those attended by the ICSI teenagers. Response rates were 56% (tested/reached) in the ICSI group and 50% (agreed/eligible) in the SC group, but information regarding health could be obtained in 63 and 72% of the ICSI and SC children, respectively. ICSI girls had a comparable resting systolic (109 ± 9 mmHg) and diastolic (64 ± 6 mmHg) blood pressure in comparison with girls in the SC group (111 ± 9 mmHg, P = 0.2 and 66 ± 7 mmHg, P = 0.05), even after adjustment for age and height. After adjustment for current body characteristics, early life and parental background factors, systolic and diastolic blood pressure remained comparable in both groups. In ICSI boys, a slightly lower systolic (113 ± 10 mmHg), but comparable diastolic (64 ± 6 mmHg) resting blood pressure was found in comparison with the SC group (116 ± 9 mmHg; P = 0.04 and 65 ± 5 mmHg; P = 0.1). After adjustment for height and age, systolic and diastolic blood pressure were comparable in both groups (P = 0.7 and P = 0.6). After correction for current body characteristics, early life and parental factors, ICSI and SC boys still had comparable systolic (difference in ICSI versus SC: -1.1 mmHg; 95% CI: -3.8-1.6; P = 0.4) and diastolic (difference in ICSI versus SC: -1.2 mmHg; 95% CI: -3.2-0.7; P = 0.2) blood pressure measurements. In the small subsample of girls and boys with continuous blood pressure readings, the systolic and diastolic blood pressure response to the stress test was not significantly different between the ICSI and SC groups even after taking into account the baseline values. Despite the rather low response rate in the ICSI group and the fact that no information on current health status could be obtained from more than a quarter of the eligible comparison group, the non-participating analysis in the ICSI as well in the SC group did not reveal differences between participating and non-participating children regarding clinical characteristics. The negative results for the sub-analysis on blood pressure response to stress should be interpreted with caution, because these data were available for only a small number of children, and the analysis may be underpowered. This result can only rule out a large effect on blood pressure responsiveness to a psychological stressor. Although our sample size appears to be appropriate, our results need confirmation by others and in larger cohorts when more data become available. Our results are the first described ever in ICSI offspring, born to parents suffering from predominantly male factor infertility. This study was supported by research grants from Fonds voor Wetenschappelijk Onderzoek Vlaanderen, Onderzoeksraad Vrije Universiteit Brussel and Wetenschappelijk Fonds Willy Gepts. Unconditional grants from MSD Belgium, Merck International, IBSA Institut Biochimique and Ferring International Center are kindly acknowledged.


Speak My Language and I Will Remember Your Face Better: An ERP Study.
Here we investigated how the language in which a person addresses us, native or foreign, influences subsequent face recognition. In an old/new paradigm, we explored the behavioral and electrophysiological activity associated with face recognition memory. Participants were first presented with faces accompanied by voices speaking either in their native (NL) or foreign language (FL). Faces were then presented in isolation and participants decided whether the face was presented before (old) or not (new). The results revealed that participants were more accurate at remembering faces previously paired with their native as opposed to their FL. At the event-related potential (ERP) level, we obtained evidence that faces in the NL were differently encoded from those in the FL condition, potentially due to differences in processing demands. During recognition, the frontal old/new effect was present (with a difference in latency) regardless of the language with which a face was associated, while the parietal old/new effect appeared only for faces associated with the native language. These results suggest that the language of our social interactions has an impact on the memory processes underlying the recognition of individuals.


Biological and chemical factors influencing shallow lake eutrophication: a long-term study.
The focus of eutrophication research has tended to be upon short-term and experimental studies. However, given the range of factors that can influence eutrophication dynamics, and that these matter over a range of time scales, some discrete, some continuous, eutrophication dynamics may only be fully investigated when long-term, time-series data are available. The present study aims to evaluate the interacting effects of abiotic processes and biotic dynamics in explaining variations of phytoplankton biomass in a eutrophic shallow lake, Barton Broad (Norfolk, UK) using a long-term data set. Multivariate statistical analysis shows that the inter-relationships between phytoplankton variability, nutrient and grazing factors were highly sensitive to seasonal periodicity. In spring phytoplankton biomass was related to phosphorus, nitrogen and silicon. In summer phytoplankton biomass was associated with phosphorus, nitrogen and zooplankton. In autumn phytoplankton was related to phosphorus, nitrogen, silicon and zooplankton. In winter, no significant relationship could be established between phytoplankton and environmental variables. This paper improves our understanding of the governing role of nitrogen, phosphorus, silicon and zooplankton upon phytoplankton variability, and hence, improves management methods for eutrophic lakes.


Factors in the 4-week Acceptance of a Computer-Based, Chronic Disease Self-Monitoring System in Patients with Type 2 Diabetes Mellitus and/or Hypertension.
Health information technology (HIT) interventions developed to support patients' self-care for chronic diseases have become popular, but people may not always accept and sustain their use. This study examined factors that affected patients' acceptance of a computer-based, chronic disease self-monitoring system over a 4-week period. A research model was developed to test the relationships between the perceived usefulness, perceived ease of use, attitude, and subjective norm and the patients' behavioral intention to use the system (i.e., acceptance). Data were collected with surveys of 42 patients with type 2 diabetes mellitus and/or hypertension at baseline, 2 weeks after implementation, and 4 weeks after implementation. Path analysis was used for model testing. Perceived usefulness affected behavioral intention indirectly at 2 weeks and directly at 4 weeks; perceived ease of use affected behavioral intention indirectly at 2 and 4 weeks; attitude directly affected behavioral intention at 2 weeks; and subjective norm affected behavioral intention indirectly at 2 weeks and directly at baseline and at 4 weeks. Patients' acceptance of HIT is affected by the factors proposed in our research model. It is suggested that healthcare stakeholders consider and address the effects of these factors and their variations over time before implementing HIT.


Effects of resveratrol on topoisomerase II-α activity: induction of micronuclei and inhibition of chromosome segregation in CHO-K1 cells.
In recent years, a great interest has emerged in resveratrol (RSV) activity in the prevention of various pathologies including cancer. We recently showed that RSV is able to interfere with topoisomerase II-α (TOPO2) activity in cancer cells, thus inducing a delay in S-phase progression with concomitant phosphorylation of the histone H2AX. TOPO2 is mainly active in proliferating cells and is involved in the resolution of supercoiled DNA and chromosome segregation during mitosis. Here, we studied the effects of RSV in CHO-K1 cells concerning to chromosome damage and segregation as a consequence of TOPO2 inhibition. We show an increase in micronuclei and in polyploid and endoreduplicated cells due to incorrect chromosome segregation. Furthermore, since incomplete segregation can also affect the normal distribution of mitotic figures, we checked mitosis progression showing an increase in metaphase in relation to ana-telophase after RSV treatment. On the whole, our data show that RSV affects chromosome stability and segregation in proliferating cells, probably interfering with TOPO2 activity.


Cell-specific aptamers and their conjugation with nanomaterials for targeted drug delivery.
Aptamers are short, single-stranded DNA or RNA sequences that can fold into complex secondary and tertiary structures and bind to various target molecules with high affinity and specificity. These properties, as well as rapid tissue penetration and ease of chemical modification, make aptamers ideal recognition elements for in vivo targeted drug delivery and attractive molecules for use in disease diagnosis and therapy. The general properties of aptamers as well as advantages over their counterpart antibodies are briefly discussed. Next, aptamer selection by cell- systematic evolution of ligands by exponential enrichment is described in detail. Finally, the review summarizes recent progress in the field of targeted drug delivery based on aptamers and their conjugation to liposomes, micelles and other nanomaterials. Advances in nanotechnology have led to new and improved nanomaterials for biomedical applications. Conjugation of nanoparticles (NPs) with aptamers exploits both technologies, making aptamer-NP conjugates ideal agents for drug delivery with proven therapeutic effects and the reduction of toxicity to normal tissue. The use of multivalent aptamer-conjugated nanomaterials represents one of the new directions for drug development in the future; as such, continuing studies of these multivalent aptamers and bioconjugates should result in important clinical applications in targeted drug delivery.


Symbiosis in eukaryotic evolution.
Fifty years ago, Lynn Margulis, inspiring in early twentieth-century ideas that put forward a symbiotic origin for some eukaryotic organelles, proposed a unified theory for the origin of the eukaryotic cell based on symbiosis as evolutionary mechanism. Margulis was profoundly aware of the importance of symbiosis in the natural microbial world and anticipated the evolutionary significance that integrated cooperative interactions might have as mechanism to increase cellular complexity. Today, we have started fully appreciating the vast extent of microbial diversity and the importance of syntrophic metabolic cooperation in natural ecosystems, especially in sediments and microbial mats. Also, not only the symbiogenetic origin of mitochondria and chloroplasts has been clearly demonstrated, but improvement in phylogenomic methods combined with recent discoveries of archaeal lineages more closely related to eukaryotes further support the symbiogenetic origin of the eukaryotic cell. Margulis left us in legacy the idea of 'eukaryogenesis by symbiogenesis'. Although this has been largely verified, when, where, and specifically how eukaryotic cells evolved are yet unclear. Here, we shortly review current knowledge about symbiotic interactions in the microbial world and their evolutionary impact, the status of eukaryogenetic models and the current challenges and perspectives ahead to reconstruct the evolutionary path to eukaryotes.


The mechanism of PLA microparticle formation by water-in-oil-in-water solvent evaporation method.
Microparticles containing ovalbumin as a model protein drug were prepared using poly(L-lactide; PLA) with a water-in-oil-in-water emulsion/solvent evaporation technique. The dispersed phase was PLA dissolved in dichloromethane (DCM), and the continuous phase was water-containing polyvinyl pyrolidone (PVP) as stabilizer with sodium chloride. Microparticle characteristics, loading efficiencies, protein distribution in microparticles, and in-vitro release properties were investigated. The OVA leaking into the continuous phase during the formation of microparticle by DCM evaporation was also evaluated. Results show that OVA was successfully entrapped in the microparticles with trapping efficiencies up to 72%, loading level 8.7% w/v, and particle size 14 microm. The semi-solid suspension changes to a solid particle happened during a 10-min period. Total protein-leaking amount was reduced after addition of NaCl in the continuous aqueous phase, which resulted from reducing the solidification time and protein-leaking rate. Using 5% w/v NaCl in the continuous phase resulted in higher loading content (87.2 +/- 1.0 microg/mg), and loading efficiency (72.2%), which resulted from more protein in the deeper layer (50.2 +/- 2.3 microg/mg) and higher microparticle yield (75.2%) than without NaCl (loading content: 74.0 +/- 1.0 microg/mg; loading efficiency 51.8%; deeper layer content: 18.3 +/- 3.5 microg/mg; yield: 63.6%). These results constitute a step forward in the improvement of existing technology in controlling protein encapsulation and delivery from microparticles prepared by the multiple emulsion solvent evaporation method.


Characterization of Chlamydia trachomatis l2-induced tyrosine-phosphorylated HeLa cell proteins by two-dimensional gel electrophoresis.
Chlamydia trachomatis is an obligate intracellular bacteria, inducing its own uptake in nonprofessional phagocytes either by phagocytosis or pinocytosis. We have previously shown that C. trachomatis L2 induces tyrosine phosphorylation of eukaryotic proteins upon their entry by phagocytosis. In this paper we characterize the tyrosine-phosphorylated proteins by two-dimensional gel electrophoresis. In immunoblotting with anti-phosphotyrosine antibodies of C. trachomatis L2-infected HeLa cells, but not with uninfected cells, two rows of spots were observed with a molecular mass of 69 and 71 kDa and pI from 5.0 to 5.2. In addition, a single spot of 100 kDa and pI 6.2 was observed.


Mycophenolate mofetil in primary glomerular diseases.
The treatment of primary glomerular diseases is highly variable and is often complicated due to drug resistance, relapses and drug toxicity. Various immunosuppressive drugs have been tried, but there is as yet no superiority of any single drug. Mycophenolate mofetil is a relatively new drug which has shown some superiority in renal transplantation and lupus nephritis. It has an advantage of relatively less side effects with no nephrotoxicity. This article reviews the recent literature on the effect of this drug in managing primary glomerular diseases.


A simplified method for staining mast cells with astra blue.
The copper phthalocyanin dye astra blue has been used to stain differentially mast cells of the intestine; however; the procedure has not been used widely because of the difficulty in preparing and using the dye solution. Described here is a simple, reliable, and consistent method for selectively staining mast cells using a dye solution that may be prepared in any laboratory without the aid of sophisticated pH metering equipment. Astra blue is mixed with an alcoholic solution containing MgCl2-6H2O and the pH indicator pararosaniline hydrochloride. Concentrated hydrochloric acid is added dropwise, changing the dye mixture from purple to violet and then to blue. In this low range the weakly ionizing ethanol provides a more stable hydrogen ion concentration than the corresponding aqueous solutions used previously. Alcoholic acid fuchsin is a convenient counterstain, and this simple procedure then provides good contrast between the blue staining mast cell granules and the red tissue background.


Suppression of mitochondrial respiration with auraptene inhibits the progression of renal cell carcinoma: involvement of HIF-1α degradation.
Renal cell carcinoma (RCC) progression resulting from the uncontrolled migration and enhanced angiogenesis is an obstacle to effective therapeutic intervention. Tumor metabolism has distinctive feature called Warburg effect, which enhances the aerobic glycolysis rapidly supplying the energy for migration of tumor. To manipulate this metabolic change characteristic of aggressive tumors, we utilized the citrus extract, auraptene, known as a mitochondrial inhibitor, testing its anticancer effects against the RCC4 cell line. We found that auraptene impaired RCC4 cell motility through reduction of mitochondrial respiration and glycolytic pathway-related genes. It also strongly disrupted VEGF-induced angiogenesis in vitro and in vivo. Hypoxia-inducible factor 1a (HIF-1a), a key regulator of cancer metabolism, migration and angiogenesis that is stably expressed in RCCs by virtue of a genetic mutation in the von Hippel-Lindau (VHL) tumor-suppressor protein, was impeded by auraptene, which blocked HIF-1a translation initiation without causing cytotoxicity. We suggest that blockade HIF-1a and reforming energy metabolism with auraptene is an effective approach for suspension RCC progression.


Polarimetry of uncoupled light on the NIF.
Polarimetry has been added to the full aperture backscatter diagnostic on the NIF. Wollaston prisms are used to sample a small region of a beam's backscatter, effectively separating it into two linear polarizations, one of which is parallel to the incident beam. A time-averaged measurement of each polarization is obtained by imaging the separated spots off of a scatter plate. Results have improved understanding of crossed beam energy transfer, glint, and sidescatter, and motivated plans to upgrade to a time-resolved polarimeter measuring the full Stokes vector.


Anaphylaxis to Beluga caviar.
Fish roe is an extremely rare cause of anaphylaxis and although its consumption has increased in recent years. We described the case of a 59-year-old man, who experienced an anaphylactic reaction after consuming caviar. Skin prick-test were performed with Beluga caviar, salmon caviar, cod, salmon, hen egg yolk and egg white, ovalbumin, ovomucoid, shrimp and mold. Only SPT to Beluga caviar was positive. The absence of sensitization to fish and hen egg was confirmed by undetectable specific IgEs to cod, parvalbumin (Gad c 1 and Cyp c 1), egg yolk and egg white, ovalbumin and ovomucoid. An immunoblot was also performed and showed an IgE-reactive band indicated that the patient was sensitized to a 26 kDa protein in Beluga caviar. In the present case, immunoblotting of the patient's serum revealed a single IgE-reactive band at 26 kDa band, which does not appear to correspond to the previous cases.


Type-II Ising Superconductivity and Anomalous Metallic State in Macro-Size Ambient-Stable Ultrathin Crystalline Films.
Recent emergence of two-dimensional (2D) crystalline superconductors has provided a promising platform to investigate novel quantum physics and potential applications. To reveal essential quantum phenomena therein, ultralow temperature transport investigation on high-quality ultrathin superconducting films is critically required, although it has been quite challenging experimentally. Here, we report a systematic transport study on the ultrathin crystalline PdTe2 films grown by molecular beam epitaxy (MBE). Interestingly, a new type of Ising superconductivity in 2D centrosymmetric materials is revealed by the detection of large in-plane critical field more than 7 times the Pauli limit. Remarkably, in a perpendicular magnetic field, we provide solid evidence of an anomalous metallic state characterized by the resistance saturation at low temperatures with high-quality filters. The robust superconductivity with intriguing quantum phenomena in the macro-size ambient-stable ultrathin PdTe2 films remains almost the same for 20 months, showing great potentials in electronic and spintronic applications.


Cutting Thick Sections Using a Vibratome.
Sectioning with a vibrating microtome (vibratome) is a valuable procedure for generating thick sections that can be used for immunohistochemistry and in situ hybridization. It is particularly useful for revealing histological and 3D detail in tissues and embryos that have been subjected to various whole-mount histological procedures such as β-galactosidase and alkaline phosphatase staining, and fluorescent and DAB (diaminobenzidine) immunostaining. Vibratome sectioning does not involve any harsh organic solvents and is therefore suited for processing specimens stained with fluorescent antibodies or dyes. In addition, live tissue can be sectioned for subsequent culture, manipulation, and live imaging. Very few materials are required for vibratome sectioning, and it is a relatively straightforward procedure that is quickly mastered. This protocol describes basic vibratome sectioning that can be used for any staining procedure typically used in histology.


[Analysis of differentially expressed genes between resuscitating and active Mycobacterium tuberculosis].
To screen key genes of dormant M. tuberculosis for resuscitation. M. tuberculosis H37Rv strain cultured for 20 days in 7H9 liquid medium was used as active bacteria. Dormant bacteria were obtained by cultivating active bacteria hermetically at 37 degrees C using methylene blue as the indicator of oxygen free until the blue medium became colorless. Then resuscitation promoting factors were added to the culture and the bacteria were cultivated for 3 days to be resuscitated. RNA was extracted from active bacteria and resuscitating bacteria, disposed of DNA in RNA with DNase I , and mRNA was purified and then were hybridized using suppression subtractive hybridization (SSH) technique. Differentially expressed genes between resuscitating M. tuberculosis and active M. tuberculosis were identified by PCR, cloning, and sequence alignment. Identification of the differentially expressed genes was performed by real-time quantitative PCR. High or specifically expressed genes as tester had been obtained by SSH in correctitude reaction (active M. tuberculosis as tester) and reverse reaction (dormant M. tuberculosis as tester). These genes were cloned into plasmid PGEM-T Easy, and 78 positive bacteria in correctitude reaction and 46 positive bacteria in reverse reaction were obtained. The positive bacteria were amplified by PCR with T7 and M13 primer, and 66 positive bacteria ( >350 bp) in correctitude reaction and 39 positive bacteria ( > 350 bp) in reverse reaction were obtained. After sequencing, 30 positive sequences in correctitude reaction and 21 positive sequences in reverse reaction were obtained. Twenty and 7 high or specifically expressed genes were finally identified in active and resuscitating M. tuberculosis respectively by searching in Genbank. These genes were classified into 8 categories. Real-time quantitative PCR demonstrated that the quantity of 7 high or specifically expressed genes in resuscitating bacteria was more than 4 times that in active bacteria. Differentially expressed genes between resuscitating and active M. tuberculosis were identified using SSH technique and the results may help exploring key genes and mechanisms of dormant M. tuberculosis for resuscitation.


Ceftaroline fosamil for treatment of diabetic foot infections: the CAPTURE study experience.
To ascertain which demographic, clinical, and microbiological factors might affect clinical outcomes of patients with diabetic foot infections, excluding known osteomyelitis, by analysing Clinical Assessment Program and Teflaro® Utilization Registry study data of patients treated with ceftaroline fosamil. At participating study centres, we collected data by randomized selection and chart review, including patient demographics, co-morbidities, infecting pathogens, antibiotic use, surgical interventions, and clinical response. Evaluable patients were those with data sufficient to determine clinical outcome. Clinical success was defined as clinical cure with no use of other antibiotics or clinical improvement with a switch to oral antibiotic therapy at the end of intravenous ceftaroline fosamil treatment. Among 201 patients (mean age 61.7 years, mean body mass index 33.2 and 57% male patients), 40% had peripheral vascular disease. Prior antibiotic therapy had been given to 161 (80%) of the patients, most commonly with vancomycin and/or piperacillin-tazobactam. Patients received ceftaroline fosamil for mean duration of 6.1 days (range 1-30), as monotherapy in 130 (65%) patients and concurrently with other antibiotics in 71 (35%). Bacterial pathogens were identified in 114 (57%) of the patients; methicillin-resistant Staphylococcus aureus and methicillin-sensitive S. aureus were isolated from 56 (49%) and 28 (25%) of culture-positive patients respectively. Clinical success was noted in 81% of patients and was not significantly associated with co-morbidities, pathogen type, or need for surgical intervention. Ceftaroline fosamil treatment of diabetic foot infections was associated with high clinical success, including inpatients with obesity, co-morbidities, or methicillin-resistant Staphylococcus aureus or mixed infections or requiring surgical intervention.


Cultivation of plant cells in a stirred vessel: effect of impeller design.
Suspension cultures of Nicotiana tabacum were grown in a batch fermentor using different agitation systems. The effects of the impeller type, size, and agitation speed on the productivity of cell mass and secondary metabolites (phenolics) have been investigated. The use of a large, flat-bladed impeller (diameter 7.6 cm; width 14.0 cm) improved culture growth significantly over systems using a regular, flat-bladed impeller (diameter 5.6 cm; width 1.5 cm). An impeller of the same dimensions as the 14.0-cm-wide, large, flat-bladed impeller with sail cloth blades yielded a higher maximum growth rate in the exponential phase but resulted in a longer lag phase. Overall (intracellular and extracellular) phenolics concentration showed a direct relationship to culture growth rate whereas extracellular concentrations were a function of agitation conditions. Power consumption and flow pattern studies were also completed to further characterize the different impellers tested.


Photostability of pentacene and 6,13-disubstituted pentacene derivatives: a theoretical and experimental mechanistic study.
Computational and experimental studies have been performed to investigate the photostability of a series of 6,13-bis(arylalkynyl)-substituted pentacenes in the presence of oxygen. These studies indicate that photostabilization occurs through a selective LUMO orbital stabilization as has been seen previously for 6,13-bis(triisopropylsilylethynyl)pentacene. Marcus theory analysis suggests that the difference in vibrational reorganization energies across all compounds is small and that the thermodynamic driving force for forward electron transfer is primarily responsible for the observed photostabilization.


Stable Isotope Labeling by Amino Acids in Cell Culture (SILAC)-Based Quantitative Proteomics and Phosphoproteomics in Fission Yeast.
Modern mass spectrometry (MS)-based approaches are capable of identifying and quantifying thousands of proteins and phosphorylation events in a single biological experiment. Here we present a (phospho)proteomic workflow based on in-solution proteome digestion of samples labeled by stable isotope labeling by amino acids in cell culture (SILAC) and phosphopeptide enrichment using strong cation exchange (SCX) and TiO2 chromatographies. These procedures are followed by high-accuracy MS measurement on an Orbitrap mass spectrometer and subsequent bioinformatic processing using MaxQuant software.


[Alfred Kohn, professor of histology at German University in Prague].
Prof. Kohn (1867-1959) was the head of the Institute of Histology at the Medical Faculty of German University in Prague for 26 years. In 2007 we commemorated his 140th birthday, and 2009 we will remember the 50th anniversary of his death. He entered the history of medicine by discovery of nature and origin of parathyroid glands and by pioneer research into chromaffin cells and sympathetic paraganglia. Kohn's papers on the pituitary, interstitial cells of testes, and ovaries are also related to endocrinology. All his studies are based on descriptive and comparative histological and embryological observations. Kohn was twice the dean of German Medical Faculty, and a member or honorary member of many important scientific societies. He was repeatedly nominated for Nobel Prize for physiology and medicine. For his Jewish origin he was expelled from Deutsche Gesellschaft der Wissenschaften und Künste für die Tschechoslowakische Republik in 1939 and transported to Terezin ghetto in 1943. After the war he lived in Prague. On the occasion of his 90th birthday he was elected honorary president of Anatomische Gesellschaft and awarded by the Czechoslovak Order of Labour. Alfred Kohn died in 1959. He was one of the outstanding personalities that Prague gave to the world of science.


Engaging Pharmacy Students, Residents, and Fellows in Antimicrobial Stewardship.
Antimicrobial stewardship programs are mainly established by infectious diseases physicians and infectious diseases-trained clinical pharmacists with the goal of optimizing patients' outcomes while halting antimicrobial resistance, decreasing adverse events, and controlling health care cost. The role of the infectious diseases-trained clinical pharmacist in antimicrobial stewardship is well established; however, there are not enough formally trained pharmacists to assume the challenging responsibilities of the steward coordinator. The purpose of this article was to review the available literature and resources and propose a model to engage introductory pharmacy practice experience students, advanced pharmacy practice experience students, postgraduate year (PGY) 1 pharmacy residents, PGY2 infectious diseases pharmacy residents, and PGY2 or PGY3 infectious diseases pharmacy fellows in antimicrobial stewardship. Further studies are needed to assess and document the impact of pharmacy students and postgraduate trainees on antimicrobial stewardship programs.


Cloning and characterization of the Arabidopsis cyclic phosphodiesterase which hydrolyzes ADP-ribose 1'',2''-cyclic phosphate and nucleoside 2',3'-cyclic phosphates.
In eukaryotic cells, pre-tRNAs spliced by a pathway that produces a 3',5'-phosphodiester, 2'-phosphomonoester linkage contain a 2'-phosphate group adjacent to the tRNA anticodon. This 2'-phosphate is transferred to NAD to give adenosine diphosphate (ADP)-ribose 1", 2"-cyclic phosphate (Appr>p), which is subsequently metabolized to ADP-ribose 1"-phosphate (Appr-1"p). The latter reaction is catalyzed by a cyclic phosphodiesterase (CPDase), previously identified in yeast and wheat. In the work presented here, we describe cloning of the Arabidopsis cDNA encoding the 20-kDa CPDase that hydrolyzes Appr>p to Appr-1"p. Properties of the bacterially overexpressed and purified Arabidopsis enzyme are similar to those of wheat CPDase. In addition to their transformation of Appr>p, both enzymes hydrolyze nucleoside 2',3'-cyclic phosphates to nucleoside 2'-phosphates. For the Arabidopsis CPDase, the apparent Km values for Appr>p, A>p, C>p, G>p, and U>p are 1.35, 1.34, 2.38, 16.86, and 17.67 mM, respectively. Southern analysis indicated that CPDase in Arabidopsis is encoded by a single copy gene that is expressed, at different levels, in all Arabidopsis organs that were analyzed. Indirect immunofluorescence, performed with transfected protoplasts, showed that CPDase is localized in the cytoplasm. Based on substrate specificity and products generated, the plant enzyme differs from other known cyclic phosphodiesterases. The Arabidopsis CPDase does not have recognizable structural similarity or motifs in common with proteins deposited in public data bases.


Experimental climate warming enforces seed dormancy in South African Proteaceae but seedling drought resilience exceeds summer drought periods.
Two hypotheses-that elevated night-time temperatures due to climate warming would enforce post-fire dormancy of Proteaceae seed due to low moisture, and that periods without rain during summer would exceed desiccation periods tolerated by Proteaceae seedlings-were tested empirically. Enforced dormancy, i.e., the inability to germinate due to an environmental restraint, was tested by measuring seed germination in 11 Proteaceae species in experimental mesocosms whose soils were artificially elevated by 1.4 and 3.5 °C above ambient by far-red wavelength filtered infrared lamps. Diminished totality of germination and velocities were observed in 91 and 64%, respectively, of the Proteaceae species tested. Drought resilience was tested in one-year-old seedlings of 16 Proteaceae species by withholding water from potted plants during summer in a greenhouse. The most drought-resilient Proteaceae species displayed the lowest initial transpiration rates at field capacity, the smallest declines in transpiration rate with decreasing soil water content, and the lowest water losses by transpiration. Projected drought periods leading to the complete cessation of transpiration in all Proteaceae species greatly exceeded the number of days without rain per month during summer in the current distribution ranges of those species. It was therefore concluded that enforced seed dormancy induced by elevated night-time temperatures is the post-fire recruitment stage of Proteaceae that is most sensitive to climate warming.


Specific, sensitive and accurate quantification of albumin, retinol binding protein and transferrin in human urine and serum by zone immunoelectrophoresis assay (ZIA).
For zone immunoelectrophoresis assay (ZIA) glass tubes, ID 2 mm and 90 mm high, are filled to 2/3 with buffer containing agarose and antibodies against the protein to be quantified, each sample being pipetted on top of separate agarose gel rods. On electrophoresis at 35-150 V for several hours, the sample proteins enter the gel with resultant immunoprecipitates, visualized by staining. The extension of each immunoprecipitation zone from the upper gel surface (measured with a ruler) is directly proportional to the amount of protein in each sample and can easily be quantitated by comparison with a linear calibration curve. ZIA can be used for quantification of several proteins in blood serum and plasma as well as in urine, as is illustrated for albumin, retinol-binding protein (RBP) and transferrin. The recovery of the pure proteins added to urine is often close to 100%. ZIA has many advantages: (i) simple apparatus and procedure (no gel punching nor cooling), (ii) minimal antiserum consumption (1 mL may allow > 1000 assays), (iii) electrophoresis can be performed within a few hours or overnight, (iv) low coefficient of variation (often < 4%), (v) linear calibration curves, (vi) low detection limit (< 20 ng/mL), (vii) wide concentration ranges, (viii) no kits nor unique antisera preparation are required, and (ix) good agreement with the results from other methods.


Living on the edge: assessing the extinction risk of critically endangered Bonelli's eagle in Italy.
The population of Bonelli's eagle (Aquila fasciata) has declined drastically throughout its European range due to habitat degradation and unnatural elevated mortality. There are less than 1500 breeding pairs accounted for in Europe, and the species is currently catalogued as Critically Endangered in Italy, where the 22 territories of Sicily, represent nearly 95% of the entire Italian population. However, despite national and European conservation concerns, the species currently lacks a specific conservation plan, and no previous attempts to estimate the risk of extinction have been made. We incorporated the most updated demographic information available to assess the extinction risk of endangered Bonelli's eagle in Italy through a Population Viability Analysis. Using perturbation analyses (sensitivity and elasticity), and a combination of demographic data obtained from an assortment of independent methods, we evaluated which demographic parameters have more influence on the population's fate. We also simulated different scenarios to explore the effects of possible management actions. Our results showed that under the current conditions, Bonelli's eagle is expected to become extinct in Italy in less than 50 years. Stand-alone juvenile mortality was the most critical demographic parameter with the strongest influence on population persistence with respect to other demographic parameters. Measures aimed at either decreasing juvenile mortality, adult mortality or decreasing both juvenile and adult mortality resulted in equivalent net positive effects on population persistence (population growth rate λ>1). In contrast, changes aimed at increasing breeding success had limited positive effects on demographic trends. Our PVA provides essential information to direct the decision-making process and exposes gaps in our previous knowledge. To ensure the long-term persistence of the species in Italy, measures are urgently needed to decrease both adult mortality due to poaching and juvenile mortality due to nest plundering, the top ranking mortality causes.


The foaming inhibitor on Nocardia and alike (FIONA) process.
A new process to abate foam-causing micro-organisms of the genus of Nocardia sp. and alike was developed in the Sha Tin Sewage Treatment Works of Hong Kong in 2002 under an in-house research and development study. The new FIONA process relates to a process of inhibiting the growth of the foam-causing micro-organisms of genus Nocardia sp. and alike, which are commonly found in activated sludge sewage treatment process with nutrient removal. The Sha Tin Sewage Treatment Works is the largest secondary sewage treatment works in Hong Kong with nitrogen removal capability. It has been suffering from Nocardia foam since its commissioning in 1982, which had led to consistent non-compliant events. The new process has been put into full scale application since 2002 and its foaming abatement effect is very effective; resulting in resumption of full compliance with the discharge licence since November 2003. The FIONA Process basically comprises a chemical dosing system and a reaction zone with a mean hydraulic retention time of 1 hour. The dosing point of the Process can be at upstream sewage pumping stations as well as the inlet works of the sewage treatment works. The dosing chemicals are to create an anoxic environment in the sewage so as to boost up the removal of the readily biodegradable substrates, which are favourable substrates of the foam-causing micro-organisms, in the sewage prior to entering the bioreactors. In such way, it will help out-compete the foam-causing micro-organisms in the bioreactors. Full scale dosing results in the Sha Tin Sewage Treatment Works from 2002 to 2004 had demonstrated that the previous year-round appearance of the Nocardia foam in the bioreactors had been greatly abated to an extent from little to moderate appearance only from January to April with complete Nocardia foam disappearance from May to December. The dosing chemical being used is calcium nitrate at dosing rates from 15 to 50 mL of aqueous calcium nitrate at 50% concentration by weight (equivalently 50 to 150 mM of calcium nitrate) per m3 of sewage. For other metallic nitrate salts, the nitrate mass content must be equivalent to the nitrate mass of calcium nitrate at the above dosing range. For hydrogen peroxide, it is believed the same effect would occur, however, there is no practical data available. A theory for the FIONA Process based on the bio-selector effect is also proposed albeit further research is necessary for its substantiation.


Characteristics of a dust trajectory sensor.
Trajectories of cosmic dust particles are determined by the measurement of the electrical signals that are induced when a charged grain flies through a position-sensitive electrode system. A typical dust trajectory sensor has four sensor planes consisting of about 16 wire electrodes each. Two adjacent planes have orthogonal wire directions. The sensor is highly transparent and mechanically robust, provides a large sensitive area, large field of view, and can, at least in principle, achieve unlimited precision. While a sensor model had already undergone limited testing in the dust laboratory, its response as a function of position and angle of incidence of the trajectory and as a function of sensor dimensions was generally unknown. To better understand its characteristics, the operation of a sensor model consisting of three planes and seven wires per plane was simulated using the COULOMB computer program. We show that the response of the reduced model can be applied to a model with more planes and more wires per plane. The effect of a trajectory's position and angle on the signal strength is discussed as well as the influence of geometrical parameters such as wire diameter, distance between wire planes, and wire length. We found a greater effect of the wire diameter on the signal strength, and a lesser effect of the plane distance, than expected. A set of similarity rules is provided for the design of a larger sensor. Finally, we discuss the optimization of the sensor for different applications.


Nurse education in higher education: understanding cultural barriers to progress.
Nurse education is established in higher education but nurse academics remain concerned about nursing's lack of equal status within the academy. This paper reports findings of a small study of nurse lecturers' views which support other published studies. It argues that cultural factors which contribute to nursing's problems gaining equal status include anti-intellectualism within nursing and academic denigration of practice. These cultural factors are linked to the history of women in higher education, the separation between intellectual education and practical, skill-based training, the low status of caring courses and the resulting mutual denigration of culturally opposed groups. Anti-intellectualism in nursing can be seen as a defensive reaction against an academic culture that defines practical activity as inferior to abstract thinking skills. This can lead to limited educational opportunities to examine the structural and cultural context of nursing. In Freire's view, this is a necessary part of education for freedom. Current cultural change, in nursing and higher education, including an emphasis on learning outcomes and transferable skills, provides new opportunities for nursing to contribute to educational change. Removing cultural barriers to the educated nurse is a responsibility shared by universities and by the nursing profession.


Towards rational midwifery service planning.
Although the work reported here began at health district level, even a casual perusal of published statistics reveals a quite bizarre situation when viewed from a manpower planning perspective. The quite considerable effort involved in producing state-certified midwives seems, on the surface at least, to be excessive given the number gainfully employed in that profession. The national situation with respect to trends in the birth rate is examined and a somewhat surprising seasonal effect identified. This material is then used to estimate the likely situation to be encountered at local level and in particular the effect at different levels of bed provision. In an attempt to translate these estimated births into workload figures recourse was made to regression analysis. Data from 417 maternity units relating both to outputs and inputs were secured, but the subsequent analysis proved abortive due to the high correlation which exists between the variables. Estimates were therefore derived from the work of other authors.


[The relationship between postoperative body temperature for 24 hours and central nervous system dysfunction in patients of selective cerebral perfusion].
Postischemic hyperthermia is known to exert detrimental effect on neurological outcome even 24 hours after brain ischemia in animal experiments. The purpose of this study is to investigate the effect of postoperative hyperthermia in cardiac surgery. We studied consecutive patients in elective or emergency cardiac surgery with selective cerebral perfusion. We recorded body temperature (BT) during 24 postoperative hours and JCS at discharge from ICU. BT was higher in JCS III group than in JCS I and II group (P < 0.05). The results indicated that postoperative BT was associated with consciousness disturbance in cardiac surgery with selective cerebral perfusion. Significant BT elevation during postoperative 24 hours in ICU may be due to brain injury such as infarction or bleeding during selective cerebral perfusion. Postoperative hyperthermia may accelerate penumbra around infarcted area to necrosis, resulting in deep coma, which may imply a possibility of managing BT for further consciousness recovery.


Nucleophilic aromatic substitution reactions of 1,2-dihydro-1,2-azaborine.
Could go either way: the addition of nucleophiles to the parent 1,2-dihydro-1,2-azaborine and subsequent quenching with an electrophile generates novel substituted 1,2-azaborine derivatives. Mechanistic studies are consistent with two distinct nucleophilic aromatic substitution pathways depending on the nature of the nucleophile.


Studies on the maxillary ostial function in cases with maxillary pain, intrasinusal cysts and chronic sinusitis.
The maxillary ostial function, measured as pressure transmission capacity, ostial airway resistance, equivalent ostial diameter during nasal breathing and with a constant artificial air-flow of 16.7 cm3 X S-1 into the sinus, was compared in three groups of patients. One group consisted of 7 sinuses in 6 patients with maxillary pain but without any signs of sinusitis; a second group of 6 sinuses in 6 patients with intramaxillary cysts; and a third group of 6 sinuses in 5 patients with chronic maxillary sinusitis. No impairment of the ostial function was found in groups one and two. In the third group an increased airway resistance of the ostia and small equivalent ostial diameters were found in both sitting and recumbent positions. With the pressure recording technique, the ostium can be judged as patent, non-patent, or partially obstructed, but no further grading can be done. With the pressure-flow technique the ostial function can be evaluated as ostial resistance or equivalent ostial diameters under 'physiological conditions' when the ostium is patent. With a constant artificial air-flow into the sinus the equivalent ostial diameter can be estimated even in non-patent ostia but the equivalent ostial diameters obtained do not always reflect the true functional state of the ostium.


Effect of cold exposure on serum DBH and interscapular brown adipose tissue MAO activity in hypothyroid T3- and T4-treated rats.
As the indicators of sympathetic nervous system (SNS) function, the activity of serum dopamine-beta-hydroxylase (DBH) and interscapular brown adipose tissue (IBAT) monoamine oxidase (MAO) were examined in rats that were chemically thyroidectomized (TX), treated with thyroid hormones, and exposed to cold (4 degrees C). In TX animals, body temperature (bt) significantly decreased, and relative IBAT mass increased as compared with control, euthyroid animals, independent of the ambient temperature. The bt fall in TX cold-exposed animals was more severe, provoking hypothermia after 4 h. Under the same experimental conditions, the SNS function was enhanced as judged by the increased serum DBH and IBAT MAO activities. The treatment of TX animals with T(4) and T(3) re-established the temperature (bt was at the level of controls) and sympathetic homeostasis (DBH activity was at the level of controls) in animals maintained at room temperature but not in those kept under cold conditions. T(4) and T(3) did not affect IBAT MAO activity of TX rats: It remained significantly above the control values whether the animals were maintained at room temperature or exposed to cold. In conclusion, the IBAT of TX cold-exposed rats is incapable of responding to the enhanced thermogenic needs despite the increased SNS activity and thyroid hormone substitution.


Correlating Polysulfide Solvation Structure with Electrode Kinetics towards Long-Cycling Lithium-Sulfur Batteries.
Lithium-sulfur (Li-S) batteries are promising due to ultrahigh theoretical energy density. However, their cycling lifespan is crucially affected by the electrode kinetics of lithium polysulfides. Herein, the polysulfide solvation structure is correlated with polysulfide electrode kinetics towards long-cycling Li-S batteries. The solvation structure derived from strong solvating power electrolyte induces fast anode kinetics and rapid anode failure, while that derived from weak solvating power electrolyte causes sluggish cathode kinetics and rapid capacity loss. By contrast, the solvation structure derived from medium solvating power electrolyte balances cathode and anode kinetics and improves the cycling performance of Li-S batteries. Li-S coin cells with ultra-thin Li anodes and high-S-loading cathodes deliver 146 cycles and a 338 Wh kg-1 pouch cell undergoes stable 30 cycles. This work clarifies the relationship between polysulfide solvation structure and electrode kinetics and inspires rational electrolyte design for long-cycling Li-S batteries.


Discovery and Characterization of ZL-2201, a Potent, Highly Selective, and Orally Bioavailable Small-molecule DNA-PK Inhibitor.
DNA-dependent protein kinase (DNA-PK), a driver of the non-homologous end-joining (NHEJ) DNA damage response pathway, plays an instrumental role in repairing double-strand breaks (DSB) induced by DNA-damaging poisons. We evaluate ZL-2201, an orally bioavailable, highly potent, and selective pharmacologic inhibitor of DNA-PK activity, for the treatment of human cancerous malignancies. ZL-2201 demonstrated greater selectivity for DNA-PK and effectively inhibited DNA-PK autophosphorylation in a concentration- and time-dependent manner. Initial data suggested a potential correlation between ataxia-telangiectasia mutated (ATM) deficiency and ZL-2201 sensitivity. More so, ZL-2201 showed strong synergy with topoisomerase II inhibitors independent of ATM status in vitro. In vivo oral administration of ZL-2201 demonstrated dose-dependent antitumor activity in the NCI-H1703 xenograft model and significantly enhanced the activity of approved DNA-damaging agents in A549 and FaDu models. From a phosphoproteomic mass spectrometry screen, we identified and validated that ZL-2201 and PRKDC siRNA decreased Ser108 phosphorylation of MCM2, a key DNA replication factor. Collectively, we have characterized a potent and selective DNA-PK inhibitor with promising monotherapy and combinatory therapeutic potential with approved DNA-damaging agents. More importantly, we identified phospho-MCM2 (Ser108) as a potential proximal biomarker of DNA-PK inhibition that warrants further preclinical and clinical evaluation. ZL-2201, a potent and selective DNA-PK inhibitor, can target tumor models in combination with DNA DSB-inducing agents such as radiation or doxorubicin, with potential to improve recurrent therapies in the clinic.


Some rules and examples in the treatment of incurable cancer.
Although there are more incurable than curable neoplastic diseases, less attention is given to the treatment of incurable tumours. Taking into consideration the reasons, three principles of treatment do offer themselves for the therapy of patients with incurable neoplastic disease: firstly, the attempt to extend the limits of curability; secondly, palliative treatment as a temporary relief; thirdly, symptomatic therapy. The most important method for extending curability and for palliative treatment is radiotherapy. Some examples of the efficiency of this method are given, including its use in advanced carcinoma of the larynx, carcinoma of the urinary bladder untreated by radical surgery, Wilm's tumour, and carcinoma of the thyroid.


Finite-size scaling as a way to probe near-criticality in natural swarms.
Collective behavior in biological systems is often accompanied by strong correlations. The question has therefore arisen of whether correlation is amplified by the vicinity to some critical point in the parameters space. Biological systems, though, are typically quite far from the thermodynamic limit, so that the value of the control parameter at which correlation and susceptibility peak depend on size. Hence, a system would need to readjust its control parameter according to its size in order to be maximally correlated. This readjustment, though, has never been observed experimentally. By gathering three-dimensional data on swarms of midges in the field we find that swarms tune their control parameter and size so as to maintain a scaling behavior of the correlation function. As a consequence, correlation length and susceptibility scale with the system's size and swarms exhibit a near-maximal degree of correlation at all sizes.


Can intra cytoplasmatic morphologically selected sperm injection (IMSI) technique improve outcome in patients with repeated IVF-ICSI failure? a comparative study.
Spermatozoal morphology was reported to effect fertilization, embryo quality and pregnancy results in spontaneous conception and ART. Intracytoplasmic morphologically selected sperm injection (IMSI) is an innovative, not invasive technique, which examines the sperm with no harm at a magnification of 6000 × in order to obtain optimal sperm to perform IVF-ICSI. We evaluated the efficiency of IMSI technique in patients with repeated IVF-ICSI failure of at least three cycles with no viable pregnancy and/or very poor sperm quality. All couples who performed IMSI between the years 2009 to 2012 were enrolled retrospectively to the study. Couples with male infertility who were treated with IMSI were included in the study. All their treatments were evaluated and divided into two subgroups: conventional IVF-ICSI treatment and their subsequent IMSI treatment. Demographic data, clinical parameters and outcome were recorded. The IMSI treatments were compared to previous non-IMSI treatments in terms of fertilization rates, cleavage rates, number of embryos and their quality, number of embryos transferred and pregnancy outcome. Forty-two couples were reviewed. Basic characteristics of the groups were comparable. Fertilization and cleavage rates of the two groups were comparable. The embryos quality demonstrated a trend toward superior quality (grade 1-2) embryos in the IMSI versus ICSI (60% versus 47%; p = 0.07 and 53% versus 40%; p = 0.07), respectively. Implantation and clinical pregnancy rates were significantly superior in IMSI group (19.2% versus 7.8%; p = 0.042 and 41.3% versus 10.5%; p = 0.02, respectively). Miscarriage rate was significantly higher in conventional IVF-ICSI group (100% versus 15.8%; p = 0.04), and live birth rate was significantly higher in IMSI group (0 in conventional IVF-ICSI and 34.7% per transfer in IMSI group; p = 0.003). IVF outcome of IMSI resulted in a higher implantation rate, pregnancy rate and most importantly delivery rate compare to non IMSI treated cycles.


Hemosuccus Pancreaticus and Obstructive Jaundice: Two Rare Complications of Chronic Pancreatitis Treated by Arterial Embolization.
The formation of a peripancreatic pseudoaneurysm is a rare and serious complication of chronic pancreatitis. In this report, we present the case of a 56-year-old male with a history of alcohol-related chronic pancreatitis resulting in both hemosuccus pancreaticus and obstructive jaundice due to a pseudoaneurysm of the gastroduodenal artery that was treated successfully by angiographic coiling.


Patients after atrial switch operation for transposition of the great arteries can not increase stroke volume under dobutamine stress as opposed to patients with congenitally corrected transposition.
Patients after atrial switch operation for transposition of the great arteries have limited exercise performance. Rigid atrial baffles may cause a relative preload reduction. Previous studies have had suboptimal control groups, which ideally should consist of patients with congenitally corrected transposition of the great arteries (ccTGA) without previous heart surgery, having a systemic right ventricle, but lacking rigid atrial baffles. Therefore the aim of this study was to test the impact of atrial baffles by comparing 12 atrial switch patients with 11 ccTGA patients. Systemic right ventricular stroke volume (SV), heart rate, cardiac index, and other parameters were assessed during rest and dobutamine stress magnetic resonance imaging. The most important difference between the groups was that the atrial switch patients could not increase SV during stress, whereas ccTGA patients increased it significantly. There was no difference between groups in the rise of the cardiac index. Heart rate increased significantly more in atrial switch patients than in ccTGA patients. The results support the hypothesis that atrial baffles restrict a rise in SV under dobutamine stress in patients after atrial switch operation for transposition of the great arteries.


Cortical excitability in human somatosensory and visual cortex: implications for plasticity and learning - a minireview.
The balance of excitation and inhibition plays a key role in plasticity and learning. A frequently used, reliable approach to assess intracortical inhibition relies on measuring paired-pulse behavior. Moreover, recent developments of magnetic resonance spectroscopy allows measuring GABA and glutamate concentrations. We give an overview about approaches employed to obtain information about excitatory states in human participants and discuss their putative relation. We summarize paired-pulse techniques and basic findings characterizing paired-pulse suppression in somatosensory (SI) and (VI) visual areas. Paired-pulse suppression describes the effect of paired sensory stimulation at short interstimulus intervals where the cortical response to the second stimulus is significantly suppressed. Simultaneous assessments of paired-pulse suppression in SI and VI indicated that cortical excitability is not a global phenomenon, but instead reflects the properties of local sensory processing. We review studies using non-invasive brain stimulation and perceptual learning experiments that assessed both perceptual changes and accompanying changes of cortical excitability in parallel. Independent of the nature of the excitation/inhibition marker used these data imply a close relationship between altered excitability and altered performance. These results suggest a framework where increased or decreased excitability is linked with improved or impaired perceptual performance. Recent findings have expanded the potential role of cortical excitability by demonstrating that inhibition markers such as GABA concentrations, paired-pulse suppression or alpha power predict to a substantial degree subsequent perceptual learning outcome. This opens the door for a targeted intervention where subsequent plasticity and learning processes are enhanced by altering prior baseline states of excitability.


H2S protects PC12 cells against toxicity of corticosterone by modulation of BDNF-TrkB pathway.
Corticosterone, one of the glucocorticoids, is toxic to neurons and plays an important role in depressive-like behavior and depression. We previously showed that hydrogen sulfide (H2S), a novel physiological mediator, plays an inhibitory role in depression. However, the mechanism underlying H2S-triggered antidepressant-like role is not clearly known. Brain-derived neurotrophic factor (BDNF), a neurotrophic factor, plays a neuroprotective role that is mediated by its high-affinity tropomysin-related kinase B (TrkB) receptor. In this study, to investigate the underlying mechanism of H2S-induced antidepressant-like role, we explored whether H2S could protect neurons against corticosterone-mediated cyctotoxicity and whether this protective role of H2S was involved in the regulation of BDNF-TrkB pathway. Our data demonstrated that sodium hydrosulfide (NaHS), the donor of H2S, could prevent corticosterone-induced cytotoxicity, apoptosis, accumulation of intracellular reactive oxygen species (ROS) and loss of mitochondrial membrane potential (MMP) in PC12 cells. NaHS not only induced the up-regulation of BDNF but also prevented the down-regulation of BDNF by corticosterone. It was also found that blocking BDNF-TrkB pathway by K252a, an inhibitor of TrkB, abolished the protection of H2S against corticosterone-induced cytotoxicity, apoptosis, accumulation of ROS, and loss of MMP. These results suggest that H2S protects against the neurotoxicity of corticosterone by modulation of the BDNF-TrkB pathway.


Effects of Community Richness and Competitive Asymmetry on Protozoa Evolution in Sarracenia purpurea Leaves.
AbstractPredicting evolution in natural systems will require understanding how selection operates in multispecies communities. We predicted that the amount that traits evolve in multispecies mixtures would be less than the amount that would be predicted from the additive contributions of the pairwise interactions and that subordinate species will be more likely to evolve in competitive systems than dominant species. We conducted an experimental test of these predictions using a guild of protozoans found in the water-filled leaves of the pitcher plant Sarracenia purpurea. The response to selection did not significantly change as we increased richness from monocultures to two- and four-species mixtures. In accordance with our second prediction, subordinate species demonstrated greater growth in competition after selection than before, while dominant species generally showed no response to selection. Monod-type experiments to determine minimum resource levels found that the dominant species had much higher resource requirements than the subordinate species and that the minimum resource requirements evolved to be higher in the subordinate species. Importantly, these results suggest that subordinate species evolve to become more similar to dominant species, which may involve resource use convergence. Our findings and other recent works suggest that community diversity can affect evolution in surprising ways that warrant further investigation.


Enrichment of adenosine using thermally responsive chromatographic materials under friendly pH conditions.
A thermally responsive boronate affinity chromatographic material, which showed thermal sensitivity, had been successfully applied for the enrichment and separation of cis-diol-containing compounds, and the capture and release process could be facilitated by adjusting the temperature. However, in this system, the pH of the mobile phase must be higher than 9.8, and alkaline media can lead to the degradation of labile compounds; the use of silica beads also limits its use. In this study, thermally responsive boronate affinity chromatographic material, namely poly(N-isopropylacrylamide-co-N-acryloyl-3-aminophenylboronic acid) grafted silica, was successfully prepared by atom transfer radical polymerization. Its structure was confirmed by IR spectroscopy and the graft ratio was 20.8%, determined by thermogravimetric analysis. Furthermore, the capture/release of adenosine, a cis-diol, was performed from pH 5.0-9.0 and 10-50°C. The elution of adenosine was remarkably retarded at decreased temperatures and adenosine could be captured completely at 10°C at pH values of 5.0-9.0. The enrichment of adenosine could be achieved by simply changing the temperature from 10 to 50°C. Therefore, this material not only improved the stability of the silica, but was also suitable for the capture of oxidation-sensitive biological analytes. Moreover, it could be used for the enrichment of cis-diol-containing compounds in LC with MS.


Matrix rigidity controls endothelial differentiation and morphogenesis of cardiac precursors.
Tissue development and regeneration involve tightly coordinated and integrated processes: selective proliferation of resident stem and precursor cells, differentiation into target somatic cell type, and spatial morphological organization. The role of the mechanical environment in the coordination of these processes is poorly understood. We show that multipotent cells derived from native cardiac tissue continually monitored cell substratum rigidity and showed enhanced proliferation, endothelial differentiation, and morphogenesis when the cell substratum rigidity closely matched that of myocardium. Mechanoregulation of these diverse processes required p190RhoGAP, a guanosine triphosphatase-activating protein for RhoA, acting through RhoA-dependent and -independent mechanisms. Natural or induced decreases in the abundance of p190RhoGAP triggered a series of developmental events by coupling cell-cell and cell-substratum interactions to genetic circuits controlling differentiation.


Fertility and flow cytometry study of frozen-thawed sperm in cryopreservation medium supplemented with soybean lecithin.
Semen cryopreservation can provide genetic resources for a large number of females from a small number of superior males. Optimization of cryopreservation media to achieve the highest quality of post-thaw semen is crucial. Soybean lecithin has evaluated as a plant-based cryoprotectant for substitution of egg yolk in ram semen extender. Flow cytometric and fertility assessments were applied following cryopreservation procedure in two experimental groups (SL group: extender containing 1% w/v soybean lecithin and EY group: extender containing 20% v/v egg yolk). The higher percentage of live sperm and the lower percentage of dead sperm were obtained in SL (47.66 ± 1.38, 52.33 ± 1.69, respectively) extender compared to EY (41.16 ± 1.38, 58.83 ± 1.69). For motion characteristics, plasma membrane integrity, acrosome integrity and mitochondria activity, no significant difference was observed between SL and EY extenders. In artificial insemination experiment, there was no significant difference in pregnancy rate, lambing rate and twining rate between SL and EY extenders. It can be concluded that SL extender can be an efficient alternative extender to preserve ram sperm during cryopreservation procedure without adverse effects.


Eliminating Disparities in Asthma Care: Identifying Broad Challenges in Quality Improvement.
Racial disparities in asthma care persist in New York State's Medicaid Program. African Americans with asthma experience higher rates of emergency department visits and inpatient hospitalizations, coupled with lower rates of long-term control medication use compared to other racial/ethnic groups. Within this context, and with funding from the Centers for Disease Control and Prevention, the New York State Department of Health designed and implemented the Eliminating Disparities in Asthma Care (EDAC) Collaborative to improve the quality of asthma care delivered in 7 provider sites located in Central Brooklyn, New York. EDAC was a partnership of the New York State Medicaid and Asthma Control Programs, 6 New York City-based managed care plans, and community-based health care providers. Over the 5-year funding period, improvements in documented asthma severity diagnosis and control classification were observed. This article describes the EDAC approach, successes, and challenges.


Enhanced methane production from pig slurry with pulsed electric field pre-treatment.
Intensive amount of manure produced in pig breeding sectors represents negative impact on the environment and requires optimal management. Anaerobic digestion as a well-known manure management process was optimized in this experimental study by pulsed electric field (PEF) pre-treatment. The effect of PEF on methane production was investigated at three different intensities (15, 30 and 50 kWh/m3). The results indicate that the methane production and chemical oxygen demand (COD) removal was improved by continuous escalation of applied intensity, up to 50 kWh/m3. In comparison with untreated slurry, methane production and COD removal were increased up to 58% and 44%, respectively.